Abstract

Platelets maintain hemostasis after injury, but also during inflammation. Recent studies have shown that platelets prevent inflammatory bleeding through (hem)ITAM-dependent mechanisms irrespective of aggregation during skin and lung inflammation. While the exact mechanisms underlying this process remain unknown, it was speculated that mediators released from platelet granules might be involved. Maintaining cerebral hemostasis during stroke treatment is of high clinical relevance as hemorrhage may aggravate the disease state and increase mortality. While it was shown that platelets help maintain hemostasis in the ischemic brain, their exact contribution remains ill-defined. Here we show that Unc13d-/-/Nbeal2-/- mice which lack platelet α- and dense granule secretion show no signs of hemorrhage in models of skin or lung inflammation. In stark contrast, lack of platelet granule release resulted in impaired hemostasis in the ischemic brain after transient middle cerebral artery occlusion (tMCAO) leading to increased intracranial hemorrhage and mortality. Our results reveal for the first time that platelet granule constituents are essential for maintenance of hemostasis during thrombo-inflammatory brain infarction but not experimental inflammation of the skin or lung thereby uncovering vascular bed-specific differences in the prevention of inflammatory bleeding.

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